Olfactory receptor mRNAs as lncRNAs that regulate genomic interactions

嗅觉受体 mRNA 作为调节基因组相互作用的 lncRNA

• 批准号: 10614532
• 负责人: Stavros Lomvardas
• 金额: $ 48.05万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614532
• 关键词: 3-Dimensional; Adaptor Signaling Protein; Affect; Alleles; Architecture; Binding; Binding Proteins; Biochemical; Chromatin; Chromosome Structures; Code; Complex; Data; Development; Developmental Process; Enhancers; Environment; Epigenetic Process; Experimental Genetics; Feedback; Gene Cluster; Gene Expression; Gene Family; Generations; Genetic; Genetic Enhancer Element; Genetic Transcription; Genomics; Greek; Human; In Situ; Island; Light; Link; Mediating; Messenger RNA; Molecular; Mus; Neurodevelopmental Disorder; Neuronal Differentiation; Nuclear; Nuclear Proteins; Olfactory Pathways; Other Genetics; Phase; Phase Transition; Process; Production; Property; Proteins; RNA; RNA-Binding Proteins; Receptor Gene; Regulation; Regulator Genes; Reporting; Repression; Role; Signal Transduction; Specificity; Structure; System; Transcriptional Regulation; Untranslated RNA; Yeasts; experimental study; gene translocation; genetic approach; genomic locus; in vivo; insight; interdisciplinary approach; nerve stem cell; novel; olfactory receptor; olfactory sensory neurons; programs; promoter; receptor expression; recruit; transcription factor

Abstract The monogenic, monoallelic, and seemingly stochastic transcriptional choice of one out of > 1000 olfactory receptor (OR) genes remained elusive for decades after the discovery of the largest mammalian gene family. However, in the past few years we obtained significant understanding on the molecular underpinnings of this enigmatic gene regulatory process. Specifically, we showed that OR gene clusters become heterochromatic at the early stages of olfactory sensory neuron (OSN) differentiation and then they aggregate in distinct nuclear compartments that assure their stable repression. As a result of this interchromosomal convergence, intergenic OR enhancers (known as Greek Islands) that are found in most OR gene clusters come in close nuclear proximity and form a multi-chromosomal super-enhancer that in each OSN associates with the transcriptionally active OR allele. The formation of the Greek Island hub is dependent upon the recruitment of the adaptor protein Ldb1, which is essential for the stable interchromosomal interactions between Greek Islands and for OR transcription. This intricate network of activating and repressive interchromosomal interactions, together with a feedback signal elicited by the expression of the chosen OR, likely generate the regulatory framework for transcriptional singularity. However, what remains unknown is the process by which an OR allele is recruited to the Greek Island hub and the mechanism that assures that only one OR allele will remain stably associated with a multi-chromosomal structure that contains numerous enhancer elements. Our preliminary data suggest that developmentally transient OR transcription and production of nascent OR mRNAs contribute to the recruitment of an OR allele to the Greek Island hub and to OR gene choice. Thus, we propose genetic experiments that will determine which sequences of the sense OR mRNA are required and sufficient for recruitment of trans OR enhancers, what proteins recognized the nascent OR mRNA and what contribution these proteins have to the assembly of a multi-enhancer/OR complex. These experiments not only will shed light to the enigmatic process of OR gene choice, but will also provide general molecular principles for the mechanisms that mediate genomic compartmentalization during cellular differentiation.

摘要 单基因、单等位基因和看似随机的转录选择&gt；1000嗅觉中的一个 在发现最大的哺乳动物基因家族后，受体(OR)基因几十年来一直难以捉摸。 然而，在过去的几年里，我们对这一现象的分子基础有了重大的理解。 神秘的基因调控过程。具体地说，我们发现OR基因簇在 嗅觉神经元分化的早期阶段，然后聚集在不同的核中 确保他们稳定镇压的隔间。作为这种染色体间收敛的结果，基因间 或在大多数OR基因簇中发现的增强子(称为希腊群岛)出现在紧密的核中 并形成一个多染色体超级增强子，在每个OSN中与转录上的 活动OR等位基因。希腊岛枢纽的形成取决于适配器的招募情况。 蛋白质LDB1，这是希腊群岛和希腊群岛之间稳定的染色体间相互作用所必需的 或者抄写。这个复杂的激活和抑制染色体间相互作用的网络，一起 利用由所选择的OR的表达式引发的反馈信号，可能生成调节框架 因为转录奇点。然而，仍不清楚的是OR等位基因的过程 被招募到希腊岛枢纽，以及确保只有一个OR等位基因将稳定保持的机制 与包含大量增强子元件的多染色体结构相关联。我们的预赛 数据表明，发育暂时性或新生或mRNAs的转录和产生起了作用 向希腊岛枢纽招募OR等位基因和OR基因选择。因此，我们提出了基因 确定正义或信使核糖核酸的哪些序列是必需的和足够的 反式OR增强子的招募，哪些蛋白质识别新生的OR mRNA及其贡献 这些蛋白质必须组装成一个多增强子/或复合体。这些实验不仅会让 光对神秘的OR基因选择过程，但也将提供一般的分子原理 在细胞分化过程中调节基因组区划的机制。